Interview with Gerald M. Edelman: part II.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
Gerald M Edelman
Publications and source records attributed to Gerald M Edelman.
Neural reapportionment: an hypothesis to account for the function of sleep.
Sleep is a ubiquitous component of animal life, and prolonged sleep deprivation is fatal in both vertebrates and invertebrates. The physiologic function of sleep, however, is not known. We propose here that sleep provides a period of time necessary to reapportion resources within neurons and neural systems that become sub-optimally distributed during active waking. Three specific examples of such reapportionment during sleep are suggested: (1) the return of the neurotransmitter, glutamate, to synaptic vesicles at presynaptic sites most active during waking, (2) the intracellular movement of mitochondria from neuronal processes to the cells soma where mitochondrial replication can occur, and (3) the readjustment of the level and distribution of neurotransmitters within the brainstem modulatory systems and elsewhere that must function in an integrated fashion during waking. Experimental approaches that might be utilized to test these hypotheses are suggested.
Animals↗
Reevaluation of the conclusion that IRES-activity reported within the 5' leader of the TIF4631 gene is due to promoter activity.
We previously reported that the 5' leader of the mRNA-encoding initiation factor eIF4G in Saccharomyces cerevisiae can function as a translational enhancer and as an internal ribosome entry site (IRES) when tested in cells. However, Verge and colleagues recently suggested that this sequence does not facilitate translation initiation, but inhibits translation in vitro and has promoter activity when tested in cells. We disagree with these conclusions and respond by showing that the data are most consistent with an internal initiation mechanism.
5' Untranslated Regions↗
BDNF induces translocation of initiation factor 4E to mRNA granules: evidence for a role of synaptic microfilaments and integrins.
In many cell types, translation can be regulated by a redistribution of translation initiation factors to actin-based cytoskeletal compartments that contain bound mRNAs. This process is evoked by extracellular signals and is regulated by determinants of cytoskeletal organization, such as integrins. In the present experiments, we provide evidence that similar mechanisms regulate local translation in dendrites during synaptic plasticity. Treatment of various neuronal preparations with the brain-derived neurotrophic factor (BDNF) resulted in redistribution of the critical eukaryotic initiation factor 4E (eIF4E) to an mRNA granule-rich cytoskeletal fraction isolated from detergent-solubilized samples. eIF4E linkage to cap structures mediates the recruitment of other translation factors in the initiation of translation events. Immunoprecipitation studies confirmed that eIF4E associates with mRNA granules and that BDNF increased this association. BDNF-induced redistribution of eIF4E was blocked by preincubation with either a peptide (GRGDSP) that inhibits integrin-matrix interactions or by a high concentration (20 microM) of the F-actin depolymerizing agent latrunculin A. Immunohistochemical studies in cultured neurons demonstrated that BDNF facilitated translocation of eIF4E into dendritic spines. Together, the findings suggest that BDNF regulates translation in dendrites by altering the localization of eIF4E relative to cytoskeletally bound mRNA granules. Integrins, which are known to be essential for stabilizing certain forms of synaptic plasticity, may be critical regulators of local translation events at synapses.
Actin Cytoskeleton↗
Naturalizing consciousness: a theoretical framework.
Consciousness has a number of apparently disparate properties, some of which seem to be highly complex and even inaccessible to outside observation. To place these properties within a biological framework requires a theory based on a set of evolutionary and developmental principles. This paper describes such a theory, which aims to provide a unifying account of conscious phenomena.
Consciousness↗
Isolation and identification of short nucleotide sequences that affect translation initiation in Saccharomyces cerevisiae.
In previous studies, we demonstrated the sufficiency of short nucleotide sequences to facilitate internal initiation of translation in mammalian cells. By using a selection methodology, we have now identified comparable sequences in Saccharomyces cerevisiae. For these studies, a library of constructs expressing dicistronic mRNAs with the HIS3 gene as the second cistron and 18 random nucleotides in the intercistronic region was introduced into a yeast strain in which the endogenous HIS3 gene was deleted. Untransformed cells or those containing the parent construct failed to grow on medium lacking histidine. Intercistronic sequences recovered from cells that did grow were evaluated by using various criteria. Fifty-six of the 18-nt sequences (approximately 1/400,000) functioned as synthetic internal ribosome entry sites (IRESes). The 14 most active sequences allowed growth in the presence of 0.1-0.6 mM 3-amino-1,2,4-triazole, a competitive inhibitor of the HIS3 gene product. In addition, eight sequences were identified that were not IRESes, but that enhanced HIS3 expression by an alternative mechanism that depended on the 5' end of the mRNA and appeared to involve either shunting or reinitiation. Comparisons among the 56 selected IRESes identified eight significant sequence matches containing up to 10 nucleotides. Many of the selected sequences also contained extensive complementary matches to yeast 18S rRNA, some at overlapping sites. The identification of cis sequences that facilitate translation initiation in yeast enables detailed biochemical and genetic analyses of underlying mechanisms and may have practical applications for bioengineering.
Base Sequence↗
The power of human brain magnetoencephalographic signals can be modulated up or down by changes in an attentive visual task.
This paper presents evidence indicating that the signals generated by neural responses to visual input can be either enhanced by increasing or suppressed by decreasing the area of the stimuli to which attention is directed. We used magnetoencephalography (MEG) to measure the frequency-tagged steady-state visual evoked responses of 11 subjects presented with two superimposed images flickering at different frequencies. Each image consisted of seven parallel bars of equal length; in any image, all bars were either red or green and either horizontal or vertical. At randomly chosen times during the experiments, any one of the three middle bars in either image transiently increased or decreased in width. Subjects were asked to attend to one image and ignore the other and to respond to changes in bar width in the attended image with a key press. In one condition, subject responses were required for changes in any of the three central bars of the attended image. We found that visual steady-state evoked responses to the attended image were enhanced relative to those evoked by the unattended image in this condition. In a second condition, subject responses were required for changes only in the middle bar. In this condition, the responses to the attended image were suppressed relative to those of the unattended image. These results may reflect relative differences in the synchronization and desynchronization of responding neuronal populations.
Adult↗
The ribosome filter hypothesis.
A variety of posttranscriptional mechanisms affects the processing, subcellular localization, and translation of messenger RNAs (mRNAs). Translational control appears to occur primarily at the initiation rather than the elongation stage. It has been suggested that translation is mediated largely by means of a cap-binding/scanning mechanism. On the basis of recent findings, we propose here that differential binding of particular mRNAs to eukaryotic 40S ribosomal subunits before translation may also selectively affect rates of polypeptide chain production. In this view, ribosomal subunits themselves are considered to be regulatory elements or filters that mediate interactions between particular mRNAs and components of the translation machinery. Differences in these interactions affect how efficiently individual mRNAs compete for ribosomal subunits. These competitive interactions would depend in part on the complementarity between sequences in mRNA and rRNA, as well as on structural differences among ribosomes in different cell types. By these means, translation may either be enhanced through increased recruitment of ribosomes or inhibited through strong interactions that sequester mRNAs. We propose that ribosomal filters may be important in cell differentiation and describe experimental tests for the filter hypothesis.
Models, Biological↗
The brain-derived neurotrophic factor enhances synthesis of Arc in synaptoneurosomes.
Protein synthesis in neurons is essential for the consolidation of memory and for the stabilization of activity-dependent forms of synaptic plasticity such as long-term potentiation (LTP). Activity-dependent translation of dendritically localized mRNAs has been proposed to be a critical source of new proteins necessary for synaptic change. mRNA for the activity-regulated cytoskeletal protein, Arc, is transcribed during LTP and learning, and disruption of its translation gives rise to deficits in both. We have found that selective translation of Arc in a synaptoneurosomal preparation is induced by the brain-derived neurotrophic factor, a neurotrophin that is released during high-frequency stimulation patterns used to elicit LTP. This effect involves signaling through the TrkB receptor and is blocked by the N-methyl-d-aspartate-type glutamate receptor antagonist, MK801. The results suggest there is a synergy between neurotrophic and ionotropic mechanisms that may influence the specificity and duration of changes in synaptic efficacy at glutamatergic synapses.
Animals↗
Cultured rat hippocampal neural progenitors generate spontaneously active neural networks.
We previously demonstrated that the neural cell adhesion molecule (N-CAM) inhibited the proliferation of cultured rat hippocampal progenitor cells and increased the number of neurons generated. We demonstrate here that the continued presence of fibroblast growth factor 2 along with N-CAM or brain-derived neurotrophic factor over 12 days of culture greatly increased the number of both progenitors and neurons. These progenitor-derived neurons expressed neurotransmitters, neurotransmitter receptors, and synaptic proteins in vitro consistent with those expressed in the mature hippocampus. Progenitor cells cultured on microelectrode plates formed elaborate neural networks that exhibited spontaneously generated action potentials after 21 days. This activity was observed only in cultures grown in the presence of fibroblast growth factor 2 and either N-CAM or brain-derived neurotrophic factor. Analysis of neuronal activity after various pharmacological treatments indicated that the networks formed functional GABAergic and glutamatergic synapses. We conclude that mitogenic growth factors can synergize with N-CAM or neurotrophins to generate spontaneously active neural networks from neural progenitors.
Action Potentials↗
Dendritic spines elongate after stimulation of group 1 metabotropic glutamate receptors in cultured hippocampal neurons.
Changes in the morphology of dendritic spines are correlated with synaptic plasticity and may relate mechanistically to its expression and stabilization. Recent work has shown that spine length can be altered by manipulations that affect intracellular calcium, and spine length is abnormal in genetic conditions affecting protein synthesis in neurons. We have investigated how ligands of group 1 metabotropic glutamate receptors (mGluRs) affect spine shape; stimulation of these receptors leads both to calcium release from intracellular stores and to dendritic protein synthesis. Thirty-minute incubation of cultured hippocampal slices and dissociated neurons with the selective group 1 mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) induced a significant increase in the average length of dendritic spines. This elongation resulted mainly from the growth of existing spines and was also seen even in the presence of antagonists of ionotropic receptors, indicating that activation of these receptors by mGluR-induced glutamate release was not required. Prolonged antagonism of group 1 mGluRs with (S)-alpha-methyl-4-carboxyphenylglycine (MCPG) did not result in shorter average spine length. Elongation of dendritic spines induced by DHPG was blocked by calcium chelation and by preincubation with the protein synthesis inhibitor puromycin. The results suggest that in vivo activation of group 1 mGluRs by synaptically released glutamate affects spine shape in a protein synthesis-dependent manner.
6-Cyano-7-nitroquinoxaline-2,3-dione↗
Machine psychology: autonomous behavior, perceptual categorization and conditioning in a brain-based device.
In studying brain activity during the behavior of living animals, it is not possible simultaneously to analyze all levels of control from molecular events to motor responses. To provide insights into how levels of control interact, we have carried out synthetic neural modeling using a brain-based real-world device. We describe here the design and performance of such a device, designated Darwin VII, which is guided by computer-simulated analogues of cortical and subcortical structures. All levels of Darwin VII's neural architecture can be examined simultaneously as the device behaves in a real environment. Analysis of its neural activity during perceptual categorization and conditioned behavior suggests neural mechanisms for invariant object recognition, experience-dependent perceptual categorization, first-order and second-order conditioning, and the effects of different learning rates on responses to appetitive and aversive events. While individual Darwin VII exemplars developed similar categorical responses that depended on exploration of the environment and sensorimotor adaptation, each showed highly individual patterns of changes in synaptic strengths. By allowing exhaustive analysis and manipulation of neuroanatomy and large-scale neural dynamics, such brain-based devices provide valuable heuristics for understanding cortical interactions. These devices also provide the groundwork for the development of intelligent machines that follow neurobiological rather than computational principles in their construction.
Animals↗
Brain-based devices for the study of nervous systems and the development of intelligent machines.
The simultaneous study of brain function at all levels of organization is difficult to undertake with current experimental tools. Present day electrophysiology only allows the recording of at most hundreds of neurons while an animal is performing a behavioral task. Because of this limitation and the sheer complexity of the nervous system, computational modeling has become essential in developing theories of brain function. Accordingly, our group has constructed a series of brain-based devices (BBDs), that is, physical devices with simulated nervous systems that guide behavior, to serve as a heuristic for testing theories of brain function. Unlike animal models, BBDs permit analysis of activity at all levels of the nervous system as the device behaves in its environment. Although the principal focus of developing BBDs has been to test theories of brain function, this type of modeling may also provide a basis for robotic design and practical applications.
Artificial Intelligence↗